Obesity is a serious and growing public health problem in the United States and around the world. While brief periods of positive energy balance likely occur in all people at one time or another, some individuals are able to resist environmental pressure towards weight gain, maintaining a chronic state of thinness. The central thesis of this proposal is that understanding the responses (metabolic, energetic, and behavioral) of individuals to short periods of positive energy balance produced by overfeeding, may provide clues as to the biologic mechanisms that either promote or protect against weight gain in the current environment. While long term controlled overfeeding experiments have been done for many years, no previous studies have systematically examined the effects of short-term overfeeding on direct measures of dietary fat oxidation, post overfeeding spontaneous food intake, or physical activity. Further, no previous study has examined the relationship between these variables and subsequent weight gain. It is hypothesized that those individuals who preferentially oxidize dietary fat, reduce food intake and increase physical activity following overfeeding will maintain a thin phenotype over time. Conversely, those who fail to make these adaptations will tend to gain weight over time. The proposed studies will examine the effects of a controlled eucaloric diet or 3 days of feeding 140% of basal energy on 1. The oxidation of 2 dietary fat tracers 2. Hunger, satiety, desire to eat and spontaneous food intake 3. Directly measured levels of physical activity, in a cohort of men and women enriched in individuals likely to maintain a thin phenotype and others selected for a propensity to gain weight. The cohort will then be followed for 3 years to determine the rate of weight gain in each subject. Baseline measures will be correlated with subsequent weight gain in an effort to define which adaptive responses to overfeeding best correlate with longitudinally determined weight gain. By taking a comprehensive approach to examining the responses to overfeeding and future weight changes, the proposed studies should help clarify how homeostatic regulatory mechanisms coordinately respond to a state of short-term positive energy balance. [unreadable] [unreadable]